To date, cancer treatment has been unsatisfactory. Despite the large number of anticancer therapies that have been investigated in clinical trials and the advances made in chemotherapeutic regimens, cancer treatment today is inadequate: it is not very effective and has major side effects. There is a significant unmet medical need for clinically effective, nontoxic treatments of cancer that overcome the drawbacks of conventional therapies. We need therapies with increased efficacy and reduced toxicity that can completely eliminate malignancies, ensure survival and provide patients with a better quality of life during and after treatment.
The abnormal vasculature of tumors and the resulting abnormal microenvironment are a barrier to the delivery and efficacy of antineoplatic agents. Tumor vessels have large holes in their walls, and their leakiness leads to increased interstitial pressure as well as nonuniform blood flow. Impaired blood supply and high interstitial fluid pressure interfere with the delivery of therapeutics to tumors. Hypoxia (low oxygen concentration) makes tumor cells more resistant to radiation and several cytotoxic drugs. Hypoxia also induces genetic instability and selects for cells with increased malignancy. In addition, hypoxia and low pH compromise the functions of cytotoxic immune cells.
Antiangiogenic therapies can prevent the formation of new blood vessels in and around tumors. They normalize the tumor vasculature and increase its efficiency, thus increasing the tumor uptake of drugs and oxygen, and distributing them to a larger fraction of the tumor cells. Increased penetration of drugs throughout the tumor enhances the outcome of therapy, and increased levels of oxygen enhance the efficacy of radiation and chemotherapeutic agents.
The endothelial cells that make up the tumor's blood supply are highly proliferative and are very sensitive to low doses of cytotoxic agents. Many traditional chemotherapeutics act as antiangiogenic drugs, as they affect these rapidly proliferating endothelial cells from tumor vessels. For example, cyclophosphamide, methotrexate, vinblastine, and paclitaxel have antiproliferative effects on endothelial cells at concentrations 10- to 100,000-fold lower than those required for inhibition of proliferation of tumor cells, epithelial cells, lymphocytes and fibroblasts [1]. The activated endothelial cells are genetically stable and might not develop drug resistance. Also, most normal vasculature in adults is relatively quiescent and not affected by antiangiogenic therapies.
Metronomic chemotherapy refers to the close, regular administration of relatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. Low doses of chemotherapeutic drugs (metronomic dosing) affect tumor endothelium and inhibit tumor angiogenesis. Activated endothelial cells are more sensitive to protracted, low-dose chemotherapy compared to tumor and normal cells [1]. Metronomic dosing of cyclophosphamide, 5-fluorouracil and other cytotoxic drugs was shown to be antiangiogenic [2].
The antiangiogenic effect of chemotherapy and radiation might also be mediated by impairing the mobilization, function or viability of circulating endothelial cells and endothelial progenitor cells released from the bone marrow. Circulating endothelial progenitor (CEP) cells can be mobilized from the bone marrow, enter the peripheral circulation, home in on sites of ongoing angiogenesis, incorporate into the lumen of growing sprouts, and differentiate into endothelial cells. These cells seem to be direct targets of chemotherapy, independent of whether the drugs are used in a maximum tolerated dose (MTD) or metronomic fashion [3]. CEP cell levels decrease markedly and abruptly when MTD chemotherapy is administered, but rebound rapidly during the break period between doses. This is similar to the hematopoietic rebound of other bone marrow precursor cells that are similarly affected, such as those in the granulocytic and thrombocytic lineages. Although the contribution level of marrow-derived CEPs to angiogenesis is not known, the continuous suppression of these cells could represent a major component of the antiangiogenic mechanisms of metronomic chemotherapy.
The radiation oncology community has long understood that frequent low doses offer a better therapeutic outcome than do less frequent higher doses. Whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually occur with metronomic administration of chemotherapy. In general, chronic low-dose chemotherapy alone has not led to long-term cure of drug-resistant tumors, and metronomic regimens did not significantly improve overall survival in heavily pretreated patients. Clinical studies in patients with metastatic colon cancer showed a higher response rate with continuous-infusion therapy (22% vs. 14%), but the impact on survival was minimal. Other clinical trials with low-dose or continuous-infusion chemotherapy have had limited success. There are, however, encouraging anecdotal results: for example, in a study in which drug-resistant patients with breast cancer were placed on a low-dose metronomic schedule of the same cytotoxic drug [4]. Metronomic treatments also have other advantages, such as marked cost savings and improved cost-effectiveness.